HLA DPA1, DPB1 Alleles and Haplotypes Contribute to the Risk Associated With Type 1 Diabetes
Open Access
- 27 April 2010
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 59 (8), 2055-2062
- https://doi.org/10.2337/db09-0680
Abstract
OBJECTIVE: To determine the relative risk associated with DPA1 and DPB1 alleles and haplotypes in type 1 diabetes.RESEARCH DESIGN AND METHODS: The frequency of DPA1 and DPB1 alleles and haplotypes in type 1 diabetic patients was compared to the family based control frequency in 1,771 families directly and conditional on HLA (B)-DRB1-DQA1-DQB1 linkage disequilibrium. A relative predispositional analysis (RPA) was performed in the presence or absence of the primary HLA DR-DQ associations and the contribution of DP haplotype to individual DR-DQ haplotype risks examined.RESULTS: Eight DPA1 and thirty-eight DPB1 alleles forming seventy-four DPA1-DPB1 haplotypes were observed; nineteen DPB1 alleles were associated with multiple DPA1 alleles. Following both analyses, type 1 diabetes susceptibility was significantly associated with DPB1*0301 (DPA1*0103-DPB1*0301) and protection with DPB1*0402 (DPA1*0103-DPB1*0402) and DPA1*0103-DPB1*0101 but not DPA1*0201-DPB1*0101. In addition, DPB1*0202 (DPA1*0103-DPB1*0202) and DPB1*0201 (DPA1*0103-DPB1*0201) were significantly associated with susceptibility in the presence of the high risk and protective DR-DQ haplotypes. Three associations (DPB1*0301, *0402, and *0202) remained statistically significant when only the extended HLA-A1-B8-DR3 haplotype was considered, suggesting that DPB1 alone may delineate the risk associated with this otherwise conserved haplotype.CONCLUSIONS: HLA DP allelic and haplotypic diversity contributes significantly to the risk for type 1 diabetes; DPB1*0301 (DPA1*0103-DPB1*0301) is associated with susceptibility and DPB1*0402 (DPA1*0103-DPB1*0402) and DPA1*0103-DPB1*0101 with protection. Additional evidence is presented for the susceptibility association of DPB1*0202 (DPA1*0103-DPB1*0202) and for a contributory role of individual amino acids and DPA1 or a gene in linkage disequilibrium in DR3-DPB1*0101 positive haplotypes.Keywords
This publication has 45 references indexed in Scilit:
- HLA genotyping in the international Type 1 Diabetes Genetics ConsortiumClinical Trials, 2010
- Confirmation of HLA class II independent type 1 diabetes associations in the major histocompatibility complex including HLA‐B and HLA‐ADiabetes, Obesity and Metabolism, 2009
- A Human Type 1 Diabetes Susceptibility Locus Maps to Chromosome 21q22.3Diabetes, 2008
- The Rising Incidence of Type 1 Diabetes Is Accounted for by Cases With Lower-Risk Human Leukocyte Antigen GenotypesDiabetes Care, 2008
- Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-ANature, 2007
- Electrostatic potential on human leukocyte antigen: implications for putative mechanism of chronic beryllium disease.Environmental Health Perspectives, 2003
- A Murine Monoclonal Antibody (928) Recognizing a New Epitope Formed with a Combination of HLA-DPA10201 and DPB10301 Gene ProductsHuman Immunology, 1997
- HLA antigens and age at diagnosis of insulin-dependent diabetes mellitusHuman Immunology, 1995
- Crucial role of the third and fourth hypervariable regions of HLA-DPB1 allelic sequences in the mixed lymphocyte reactionHuman Immunology, 1992
- Severe acute graft-versus-host disease by HLA-DPB1 disparity in recombinant family of bone marrow transplantation between serologically HLA-identical siblings: An application of the polymerase chain reaction—restriction fragment length polymorphism methodHuman Immunology, 1991